2 (3) benxofuranone derivatives and methods of making them



Patented July 4, 1950 2 (3JBENZOFURANONE DERIVATIVES AND METHODSOFMAKING THEM Arthur W". Weston and Marvin A. Spielman, Waukegan, 1111,assignors to Abbott Labor-w tories, Chicago, 111., a. corporation ofIllinois NoDrawing. Application Marcli- 9, 1945, Serial No. 581,952

'- 11 Claims.

1: This invention relates generally to therapeutic substances and morespecifically to derivatives of furanone which are useful asantispasmodics (substances which hav a relaxing effect on smoothmuscle).

The invention may be illustratediby the following examples:

34.5 g; (g:='grams) of'sodium" metal are-pow dered under 300 cc.(cc.-=cubic centimeters) -of-toluene b heating the sodium.-and toluenein a flask equipped with agitator. and reflux condenser, to atemperature suffi'cient to'melt thefsodium", agitating vigorously, with'cooling until the sodium particles solidify; and then diluting with2'f'1iters' of benzene. T'othis suspension is added; portion" Wise, 315'g; of3;phenyl 2(3)-benzofuranone ac: companied. by, stirring.Refl'uxingis finalllyv necj+ essary todissolve allthesodium: Aftercooling the resulting solution in an ice' bath, 227 g." of"B-diethylaminoethyh.chloride: is slowly added. The mixture is thenstirred at room temperature for 60 hours.

The reaction product is extracted with dilute hydrochloric? acid... Thehydrochloride of the product may separate as axthick oil in a,concentrated solution. The combined extracts are treated with excesssodium carbonate and the liberated base extracted in turn .with ether.By-concentrating the ether extracts and distilling the residue; there isobtained-402 gz of B -(B-diethyL' aminoethyl) -3-phenyl-2(3)-benzofuranone, Bl P;

195 C. (Cl=centigrade) at 3 mm: pressute, in anyield; Therefra-ctive-index for:the-=sodium line. at' 25 C; is 115612, customarilywritten n 2 *.:1;5612:.

' Example 1'B The addition. Ofgaseous ydrogen chloride to. a solution ofthe'ab'ove base' in" a solventsuch as. diethyl ether precipitates agummy'mass which slowly solidifies. By crystallization from anacetoneeetheri solutionthe.v crystallinee hydroch1oride; B.-' 151-152?C, obtained.

2. E xa'mpler- 1C;

The-addition ofi an excess of sulfuric acid-:to an ethereal solution ofthe baseprepared inyEx-ample 1A produces the amine hydrogen sulfate:(which might alsobe called a bisulfate); which after; crystallizationfrom: absolute alcohol meltsat -437 C.

Example 1D The methobromide, prepared by allowing the base mentioned inExample 1A to stand at room temperature with excess alcoholic methylbromide, melts after crystallization from ethyl methyl ketone at127-129" C.

Example 1E In a manner; analogous. to that disclosed? in; Example 1A,there is obtained by employing fl-dimethylaminoethyl chloride, the base3-(,8-dimethylaminoethyl) 3 pheny1-2(3) -benzofuranone, B. P. -166 C. at2 mm., 12 15700. The hydrochloride salt melts; at 209-210" C.

Example 1F Similarly; by employing "y-diethylaminopropyl chloride, thebase 3-(y-diethylaminopropyl)-3- phenyl-2(3)-benzofuranone, B. B.187-189 at 2 mm., n 1.5510 is obtained. The hydrochloride salts meltsat-171 C.

Example 1G In .a similar manner; except that the reactants arerefluxediin a. toluene solution,fthere a.re. old-- tained:

(11) By employing,' fl-di-nebutylamino' ethyl: chloride, the. base. 3'-(l3-di-nebutylamino. ethyl 3-pheny,l'-2 3) -benzofuranone, .BI PI210-212 at 2 mm., n fi 1.5383, in a 74% yield.. 'Iliel'iydrochloridesalt' melts at .1'20 -l 2l.

(2) By employing, -di-n-butylamino. propyl? chloride, the base..- 3'.-(wsdi n-butyl'amino .propyl) 3'-phenyl-2(3) -benzofi1ranone, BI. PI209-210 at. 1 mm., 15 15278. The hydrochloride. salts. melts at 13613'7.

5 g. ofr50 %f.'sodium hydridezinparafiimisiadded .-with stirring to 25ccLofLdry toluener- Aiteridilu Emm'ple 2B The hydrochloride prepared bytreating the base produced in Example 2A with ethereal hydrogen chlorideconsists of a mixture of the two possible racemic forms and melts at195-205 C.

By fractional crystallization from an acetoneether solvent the highermelting diastereoisomer, M. P. 222-224 C. is isolated.

Example 20 In an analogous manner there is obtained by employingp-diethylaminopropyl chloride, the base 1 3- (fi-diethylaminopropyl)-3-phenyl-2(3) benzofuranone, B. P. 168-169 C. at 1 mm., n 1.5590, whichhas the formula:

The mixture of the two racemic forms of the hydrochloride melts at191-203 C.

Example 3A :0 omen,

The sodium salt of 21:0 g.-of 3-phenyl-2(3)- benzofuranone ispreparedbyits gradual addition to a suspension of g. of 50% sodiumhydride-parafl'in in 200 cc. of dry benzene. After the addition of 20.0g. of 'y-morpholino-B,B-di'- methylpropyl chloride the mixture isrefluxed arid stirred for hours. Following the isolation proceduredescribed in Example 1A, the 3 (v-morpholino-,8;e-dimethylpropyl)-3-pheny1- 2(3)-benzofuranone is obtained as an oil, B. P. 219-220 C. at2 mm., 15 1.5618. The yield is 73% when corrected for the recovery ofsome of the unreacted chloroalkylmorpholine. The free base solidifiesand melts at 94.5-95.5" C. after crystallization from petroleum ether.

Example 313 The hydrochloride which maybe prepared by treatment of thebase produced in Example 3A with ethereal hydrogen chloride iscrystallized from isopropyl alcohol, and melts at 219- 220.50 C.

Example-3C In an analogous manner, except that the reaction mixture ismaintained at C. instead of refluxing, there are obtained; 3

(1) By employing e-morpholinoethyl chloride, the baseB-(pi-morpholinoethyl) -3-phenyl-2(3) benzofuranone, B. P. 225-227 C. at4 mm. in 66% yield. The base solidifies and melts at 95.5-96.5 C. Thehydrochloride melts at 211-212 C.

(2) By employing B -piperidinoethyl chloride, the base 3-(p-piperidinoethyl) -3-phenyl-2(3) benzofuranone, M. P. 88-89 C. Thehydrochloride melts at 214-215 C.

(3) By employing 'y-morpholinopropyl chloride, the base3-(*y-morpholinopropyl) -3-phenyl- 2(3)-benzofuranone having a meltingpoint of M. P., 83-84 C. The hydrochloride melts at A mixture of thesodium salt produced by the method of Example 3A from 21.5 g. of5-n-propyl- 3-phenyl-2(3) --benzofuranone produced as in Example 16 and12.0 g. of p-diethylaminoethyl chloride in 300 cc. of benzene is stirredat room temperature for 60 hours. The reaction product is worked up aspreviously mentioned in Example 1A. The5-n-propyl-3-(B-diethylaminoethyl) -3- phenyl-2(3) -benzofuranonedistills at 207-208 C. at 3 mm., 11 1.5480. The yield is 75% of the vtheoretical.

Example 4B:

The hydrochloride obtained by treating the base produced in Example 4Awith ethereal hydrogen chloride is crystallized from ethyl acetateandmelts at 131-133.

Example 40 By a procedure similar to that in Example 4A,

employing 5-methyl-3-phenyl-2(3) -benzofura-' Example 5.4

20.2 g. of 5-chloro-3-phenyl-2(3l-benzofurr anone is converted to itssodium salt as in .EX-J

ample 1A and condensed in benzene with 11.5 g. of ,e-diethylaminoethylchloride by stirring at.

room temperature for two "hours and finally re.- fiuxing for threehours. The basic fraction isolated in the foregoing manner solidifiesupon removal of the solvent. The 'yield of 5-chloro-3- (.pdiethylaminoethyl) 3 phenyl-2(3) -benzofuranone melting at 94-95" C.after crystallization from cyclohexane, is 70%.

' Example 5B Following the procedure in Example 13 the above base isconverted to the hydrochloride which can be crystallized from.ani'absolute alcohol-ether mixture. It melts, at 187--188 C.::

Example 58' Example 6A Example 63' The hydrochloride of the above basemelts at 171.5-173 C. after crystallization from acetoneether.

' Example 7A I Jz-omommoinm The condensation is carried out by stirringthe sodium salt of the 3-(m-tolyl)-2(3)-benzofuranonewith thep-diethylaminoethyl chloride at 25 C. for 18 hours. ethyl) -3 (m-tolyl)-2 (3) -benzof uranone-has B. P. 183-185 C. at'3 mm., n 1.5585.

Example 73 v The hydrochloride of the above base can be crystallizedfrom. acetone-ether and melts at 147.5-149 C.

- Example 8.4

A benzene suspension of the sodium salt from 26.0 g. of 4,5-benzo-3-phenyl-2(.3) -benzoiuranone and 13.5 g. of p-diethylaminoethyl chlorideis stirred at 25 C. for one hour, then refluxed and stirred hours.

Upon following the usual isolation procedure,

the hydrochloride of, the as-b z -aj-rg-di thyn 6 aminoethyl)-3'-phenyl-2 (3) -benzofuranone separates out during the acidicextraction-in a 59% yield. By crystallizing from isopropyl alcohol-a M.P. 184-1850. is attained.

Example 8B The free'base which is liberated by treatment of the abovesalt with sodium carbonate solidifies and melts at 98.5-99.5 C. aftercrystallization from alcohol. I

Example 9A To a suspension of the sodium salt of 2-methoxybenzylcyanide,prepared by a three-hour refluxing of 42 .5 g. "of the nitrile with 12.1g. of sodamide in 800 cc. of benzene, there is added 49.0 g. ofcyclohexyl bromide. The mixture is refluxed and stirred for 20 hours.The reaction mixture is washed with water followed by concentrationofthe benzene solution. The residual oil distills at 155-157" C. at 3 mm.There is thus obtained 43 g. of a-cyclohexyl-Z-methoxybenzyl cyanide. n1.5320, or of the theoretical amount. v

By refluxing 30 g. of a-cyclohexyl-2-methoxy benzyl cyanide with 5.9 ofsodamide in cc. of benzene for three hours, the sodium salt is formed.To the clear solution 20.3 g. of p-diethylaminoethyl chloride is addedand the refluxing and stirring continued for 20 hours.

The benzene layer is washed with water several times; Extraction withacid is followed by addition of alkali to the acid solution, extractionof the liberated base with ether, and finally removal of the ether anddistillation of theresidual oil. There is thus obtained 32.0 g. ofa-cyclohexyl-a- (B-diethylaminoethyl) -2-methoxybenzy1 cyanide'fB. P.168-170 C. at 2 mm., 11 1.5182 or 75% of theoretical amount.

A solution of 30.0 g. of oc-CYCIOhGXYI-dr-(fi-diethylaminoethyl)-2methoxybenzyl cyanide in 18-0 cc. of 48% hydrobromic acid is refluxed 45hours. The solutioni then concentrated to dryness on the steam bath andtreated with excess thionyl chloride. After removing the excess of thereagent on the steam bath, ice water and ether are added and the mixturestirred until solution is complete. The" aqueous portion is madealkaline andthe basei extracted with ether, concentrated and distilled.The 3-cyclohexyl 3 (p-diethylaminoethyl) 2(3) -benzofuranone boils at175176 C. at 3 mm. 12, 1.5284. The yield is 21.5 g. or 75% of theory.

Example 98 The hydrochloride of the basepro'duced'in Example 9A may beprepared in the usual manner and can be crystallized from ethyl acetate,M. P- 142914 Y Example 96' I In ananalogous manner by employing.S-methyl-2-methoxybenzyl cyanide as the starting ma.-.

ter'ial,[ there is obtained:

(1) By direct alkylation with fl-diethylaminm ethylchloride, an 83%yield of a-(p-diethylamie noethyl) -2-methoxy 5 methylbenzyl cyanide, B.P. 158-160 C. at 3' mm. Hydrolysis and-ring closure gives the base 3- (p-diethylaminoethyl) -5:-,, methyl-2(3)-benzoiuranone B. P, -1143 C. at

7 (2) By alkylation with n propylbromide 9. 92% yield of theintermediate a-propyl-2-methoxy 5- methylbenzyl cyanide, B. P.129130'-C. at 3 mm." Subsequent treatment with fi-diethylaminoethylfchloride gives 79% of the base@- (,d-diethylamino ethyl)-a-propyl-2-methoxy-5-methylbenzyl cya- Example A benzene solution ofthe sodium salt of 50 g. of 3-phenyl-2(3)-benzofuranone and 36 g. of 7-bromobutyronitrile is refluxed and stirred for 24. hours. Washingwith'water is followed by concentration of .the benzene solution. Theresidue of 45 'g. crystallizes from alcohol giving 3 (Y -cy anopropyl)-3.-phenyl-2 (3) benzofuranone, P. 98-99.

The foregoing nitrile, 27.7 g., is dissolved in a solution of 12 g. ofpotassium hydroxide in 100 cc. of methyl alcohol and hydrogenated at 125at'900lbs. pressure with Raney nickel. catalyst. The catalyst isremoved'by filtration and the filtrate evaporated to dryness. Ringclosure is accomplished with thionyl chloride as inExarnple 9A. This isnecessary because the alkaline re-. duction has opened thefuranone.ring,.and it must be closed again. The residue after removal ofthe solvent and excess reagent is treatedwith a small amount of water.The solidmaterial (27.8' g.) is filtered off and crystallized from. analcohol-ether mixture whereupon the hydrochloride of 3- (a-aminobutyl)-3-'phenyl-2 (3) -benZ0.- iuranone, M. P. 108110 C. is obtained.

Example 11 A mixtureof 35g. of benzyl cyanide and 10.1-g. of sodamide in200 cc. of ether is refluxed and stirred four hours. Then 28 g. of,B-diethylami:

. noethyl chloride is added and the refluxing and stirring is continuedfor 18 hours. Theether layer is washed with water, then extracted withdilute acid. Addition of alkali regeneratesthe base which is extractedwith ether, concentrated and distilled. The resulting s-diethylaminoethylbenzyl cyanide boils at 133 C. at 3 min. 11 1.5010. The yield is32.5 g. of 74% of theory.

The sodium salt of 54.0 g. of the p-diethylaminoethylbenzyl cyanide isprepared in the foregoing manner from 10.5 g. of sodamide in ethersolution.- After the addition of 24.5 g. of cyclohexene oxide, themixture is stirred and refluxed *48 hoursi Hydrolysis and isolation ofthe "basic stirred with acetone.

fraction is'c-arried -out in the usual manner. The 'basic fraction isrefluxed 30 hours with 300 cc. of 48 %'hydrobromic acid. Afterconcentrating to drynesson1the steam bath; the residual oil istreatedwfih'excess thionyl chloride. This reaction 7 product is stirredwith waterand ether. The 'water layer is then separated, made alkalineandthe r'esulting 'oil is extracted with ether which is'thenconcentrated and the residue distilled; *There is thus obtained 33 .4;g. of pure 3-(fl-diethylaminoethyl) -3-phenyl 2(3) hexahydrobenzoi'uranone. B,- .l ...199-200 C. at 4 mm, 1 1.5291.

' Example 12A .uA.-benzene solution of the sodium salt from 19 g. of3-pheny1-2(3).ebenzofuranoneand 22 g. of w-diethylaminoundecyl chlorideis refluxed for twenty hours. ,After' washing with water, the benzenevlayer is concentrated and the residual oil distilled. There is obtained3-w-(diethylaminoundecyl) -3phenyl2(3) -benzofuranone, B. P. 205-210 at0.1 mm.,.n 1.5224.

.. Emm l fi I The hydrochloride salt prepared in the"manner describedabovafor obtaining other salts is obtained as an oil which shows littletendency to crystallize.

Example 13 I \C=O phenyD-a-aminoacetic acidhydrochloride and 6 g.ofthionyl chlorideis heated on the steam bath for four hours.Thesolutionis concentrated under reduced pressure and the gummy residueThe resulting solid is filtered and ,washed with acetone; --The product3-aminoe3-pheny1-2('3) benzofuranone hydrochloride decomposes around218-220 but the range is somewhat dependent 'on the rate of heating.

Example 14 CHgCoHa I I T hei condensation. of sodium "salt from 72 g. of3- phenyl 2( 3j)ebenzoiuranone and 76.8 g. of is carried out byrefluxingthe benzene solution of the reactantsfor' th rty hours. After washingwith waterjth'e' benzene layer is concentrated and lized from alcohol.

*9 the residual e11 distilled.. The 3-lzplN-benzyl N-n-butylamino)ethyl] -3-phenyl 2(3) -ben'zo furanone has B. P. 225-227 C. at 1 mm 11.3, 1.57150 and'is obtained in a 62.5% yield.

Example 15A 7 o \C=O 24 g. of the 3-[ B(N-benzyl N-n-butylamino) ethyl]-3-phenyl-2 (3) -benzofuranone Obtained as described in Example 14, isdissolved in 50 cc. of glacial acetic acid. .Iov the solution, asuitable catalyst, such as 0.24 g. of platinum oxide is added and themixture hydrogenated at 45 lbs. pressure at 70 C. After five hours, thetheoretical amount of hydrogen is absorbed. The catalyst is removed byfiltration and the filtrate allowed to stand. The crystalline base 3-(pen-butylaminoethyl) -3-' phenyl 2(3) benzofu'ranone which separatesmelts at 103-104 C.

Example 153 By heating the base produced in Example 15A withconcentrated-hydrobromic acid, the hydrobromide salt separates as an oilwhichcrystallizes upon stirring with ether. After crystallization froman acetone-ether solvent mixture the 34-5- n-butylaminoethyl) 3 phenyl-2(3) benzof uranone hydrobromide melt; at 158-159- C.

' 'Example 16 (Intermediate) A mixture of 68 g. of p-n-propylphenol and38 g. of mandelic acid is heated in a bomb at 230 for forty-fiveminutes. poured into aqueous'10'% sodium carbonate solution and stirredwell. The oilylayer is separated and the excess p-n-propylphenol removedat 80 at 3 mm. The residue solidifies and is crystal- The3-.-phenyl-5npropyl- 2(3)-benzofuranone melts at. 56-57 new compound isthe starting material for Err-,- ample 4A.

which becomes crystalline upon stirring with The resulting oil is C.-This 10% aqueous sodium carbonate.

After crystallizing fromdilute alcohol, the "El-(r'n-tolyl) -2(3)b'en'zofura'none melts at 88 C. This new compound is the startingmaterial'for Example 7A. These compounds may be represented by theformula:

where R1 is hydrogen, hydrocarbon, preferably -alkyl, cyclo'alkyl, arylor substituted aryl or alkyl;

R3, R2; R4, R5, R6, and R7 may each be hydrogen, hydroxy, halogen, orhydrocarbon. m, n and p are each zero or a small Whole number, but notall zero; X is one or more substituents selected from the groupcomprising hydrogen, hydrocarbon, substituted hydrocarbon, or halogen,or a chain of atoms joined at its ends to two adjacent carbon atoms ofthe ring A; and Rs is'a group containing a nitrogen atom. Compounds inwhich Re is an amino or quaternary ammonium group, are preferred fortherapeutic, purposes.

Compounds in which R3 is a nitro'gen conta'ining group such as nitro,cyan'o, hydroxylamino, and 'acylamino are useful as intermediates in'thesynthesis of the preferred compounds. The ring A may be aromatic, or mayhave one or more of the double bonds reduced. The nitrogen-containingsubstituent bonded to the furanone ring maya'ls'o be a heterocyclicring.

In general, the compounds of this invention may be prepared by one oftwo methods. First, those in which R1 is an aromatic ring may beprepared by treating the appropriate 3-R1-2-(3) benz'ofu'r'anone withone chemical equivalent of an alkali metal (or of an alkali metalcompound equivalent to the metal in its reaction on the reagentsinvolved, such as the amide, alcoholate or hydride) in a suitablesolvent, such as alcohol, toluene or benzene, to form the alkali metalderivative of the 3 aryl-2-(3) benzofuranone. To this is then added thedesired aininoalkyl halide or suitable derivative or precursor and themixture stirred for several hours. The hydrohalide addition compound ofthe amine may be used instead if an additional equivalent amount ofalkali metal compound is present to liberate the base from thehydrohalide salt. If the resulting 3-substituted-3- aryl-2(3)benzofuranone contains a basic amino group it is extracted by treatingthe mixture with a dilute aqueous solution of an acid such ashydrochloric acid. The acid solution is then made alkaline by means ofan alkali carbonate such as sodium carbonate and the liberated organicbase extracted with a suitable organic solvent, such as, ether orbenzene. If, on the other hand, the 3-substituted 3-aryl-2-(3)ben'z'ofuranone does not contain a basic group, the reaction product iswashed with water and the non-aqueous layer separated. The solvent ineither case is removed by distillation and the residue may be purifiedby suitable treatment, such as, fractional distillation underreducedpressure or crystallization. Addition salts of the product may be formedby passing gaseous hydrogen halides into thereal'solutions of the bases.The addition salts may precipitate as gummy solids and may be purifiedby crystallization from a suitable solvent such as for example a mixtureof acetone and ether.

When R1 in the above formula i hydrogen, alkyl, or cycloalkyl a solutionof the appropriate 2 alkoxy .benzyl cyanide in benzene, toluene or 11othersuitable solvent is refluxed with an alkali metal or compound suchas sodium, metal, or amide or hydride to produce a suspension of the,alkalimetal derivative of the alkoxy benzyl cy-.

anide. To this suspension is then added the appropriate alkyl orcycloalkyl halide for introduction of the group R1 into the molecule andrefluxing is continued. When the reaction is complete the mixture isWashed with water, the nonaqueous layer separated and dried, and thesolvent removed by distillation. The resulting crude cyanide may bepurified by fractional distillation. This cyanide is then refluxed in asuitable solvent such as benzene or toluene with an alkali metal orcompound, to produce the alkali metal derivative of the cyanide to whichis then added the appropriate amino alkyl halide (or derivative orprecursor) and refluxing is continued until completion of the reaction.The mixture is then washed with Water several times and the nonaqueouslayer separated, If the resulting product contains a :basic group thislayer is extracted with acidulated water, this water layer is separated,made alkaline, and extracted with a suitaible solvent. The solvent isremoved by distillation and the, crude cyanide may be purified byfractional distillation or crystallization. This. substi-.

tuted cyanide is then refluxed. with 48% hydroloromic acid for severalhours and then concentrated to dryness. The residue is then treated withan excess of thionylchloride, if required to complete the ring, closure.Thionyl chloride, if used, is subsequently removed by distillation. Icewater and a suitable solvent are added to the residue and stirringcontinued until solution is complete. The aqueous portion of themixtureis made alkaline and then extracted several times with a suitablesolvent. The non-aqueous layers are combined, the solvent removed bydistillation andthe resulting substituted ben zofuranone purified Ibyfractional distillation or crystallization. It will be obvious that thewell-known modifications of an aryl group include the attaching ofadditional hydrogen atoms or other groups under conditionsv such thatone or more of the double bonds in the ring is removed; and that an arylgroup or modified aryl group may be a substituent on analkyl chain. Thephrase, substituted alkyl and substituted aryl are intended to includeall such obvious combinations.

, Pharmacology These compounds have been tested as'antispasmodic agentsand have been found to be exceedingly eflicacious in relieving smoothmuscle spasms of bothnervous and muscular origin.

Moreover these compounds are surprisingly free of some of the clinicaldisadvantages associated with atropine and .papaverine and .they exhibitfewer side reactions than some of the known antispasmodic agents. v

Other types of antispasmodics exhibit some undesirable side reactionsfrom-which the benzofuranones of this invention appear to be rela- 5contractions," whether they 'be of musculotropic or neurotropic origin.J M Some of these compounds, particularly that'of Example 1A, exert apowerful and prolonged local anesthetic effect with relatively littlelocal irritation, as compared with other known synthetic antispasmodics.To secure such-local action it is only necessary to administer thetherapeutic in such a way that itwill :be present in effectiveconcentration in the localized area where the anesthetic effect isdesired. This local anesthetic effect may in certain conditions be madeto contribute greatly to alleviation of pain, and thus :becomessynergistic with the more generalized spasmolytic action which resultsfrom the same administration. I v

The new products may be administered orally, intramuscularly,subcutaneously or intravenously and are equally effective whetheremployed in powdered form or admixed with an inertsolid diluentordiss-olved 'in a suitable liquid vehicle. They are exceedingly stablein aqueous'solution and can be stored inv that, conditionfor loneperiods without deterioration. This is in marked contrast to many othersynthetic antispasmodics.

In addition to having important'physiological properties, thesecompounds are relatively nontoxic and have a high therapeutic index. Intests conducted on the specific compound of Example 1A, the averageclinical dose has been' 50 to mg. administered either by mouthor byparenteral injection, In some cases this hasbeen continued over severalweeks without-cumulative toxic efiect. I

This compound has also been given to patients over several months withsuccess and without producing any symptoms of chronic toxicity. The drugappears to be entirely non-narcotic and prolonged administrationproducesno significant increase in tolerance. In other words, the response to agiven dosage remains substantially unimpaired.

As previously mentioned, all of these derivatives of benzofuranone areusually more soluble in water as salts than as the free bases and aretherefore administered water soluble as salts when rapid eifect isdesired. Any acid which produces a water-soluble salt and does notappreciably enhance-the toxicity is suitable foruse.

tioned in the following claims, it is intended to include both the freebaseand the salts. It will be obvious that such addition compounds asthe quaternary ammonium salts, of which the methobromide of Example 10is an illustration may be derived from any of the'other examples ofbenzofuranones and by use of other alkyl halides. These quaternaryammonium salts have been shown to have a more powerful action than thetertiary amines from which they have been produced.

'Without further elaboration, the'foregoing will so fully explain ourinvention that others may readily adapt the same for use under varyingconditions of service. It will, for instance, be obvious t hereasthe'best results obtained hitherto in preparing compounds in which R1 isaromatic, can be according to the procedure described in column 10,starting with the furanone ring already formed, whereas the othercompounds have been prepared by the process in columns and 11 in whichclosure of the furanone ring is the last step, it may under certainconditions be advantageous to form aryl substituted compounds by finalring closure or alkyl substituted compounds by addition to a previouslyformed furanone ring. Also, when R1 is a heterocyclic ring, theprocedures outlined are equally applicable.

We claim:

1. A 2(3) -benzofuranone characterized by a substituent at the3-position, in which R2 represents an alkylene group containing 2 to 11carbon atoms inclusive, and R3 and R4 are selected from the classconsisting of hydrogen and alkyl groups containing 1 to 4 carbon atomsinclusive and alkyl groups forming a cyclic group, and salts thereof.

2. A 2(3) -benzofuranone in accordance with claim 1 being furthercharacterized by a R1 substituent at the 3-position, in which R1 isselected from the class consisting of alkyl, cycloalkyl and aryl groups,and salts thereof.

3. A 3 (dialkylaminoalkyl) 3 phenyl- 2(3) benzofuranone and saltsthereof, said dialkyl group being made up of alkyl groups containing 1to 4 carbon atoms and said alkyl group being an alkylene groupcontaining 2 to 11 carbon atoms.

4. In the method of making a, 2(3)-benzofuranone in accordance withclaim 1, the improvement which comprises reacting the alkali metal saltof the benzofuranone with a compound represented by the formula whereRz, R3 and R4 represent the substituents set forth in claim 1 and Yrepresents a halogen atom.

5. In the method of making a 2(3)-benzofuranone in accordance with claim1, the improvement which comprises reacting the alkali metal salt of a2-alkoxybenzyl cyanide with a compound represented by the formula boxylgroups-in the presence of an acid condensing agent to close and form thefuranone ring.

6. The compound 3 B diethylaminoethyl-3- phenyl-2-(3) benzofuranonerepresented by the '7. The compound 3-,8-diethylaminoethyl-3-cyclohexyl-2-(3) -benzofuranone represented by the formula:

8. The compound 3 c dlethylaminoethyl-3- phenyl-2-(3) -benzofuranonemethobromide represented by the formula:

C=O (L OaHs OH:OH:N

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date Re. 22,264 Loewe Feb. 9, 19432,305,529 Hester Dec. 15, 1942 2,342,135 Gibbs Feb. 22, 1944 2,380,063Mowry July 10, 1945 OTHER REFERENCES Chemical Abstract, vol. 33, page10351.

1. A 2(3) -BENZOFURANONE CHARACTERIZED BY A